Chronic renal failure is both devastating to the individual and expensive to treat. In 1998, there were 87,000 new cases of end-stage renal disease (ESRD) in the US, taking the total patient number to 400,000. This resulted in 63,000 deaths and cost $US16.74 billion. Current treatment options for ESRD are dialysis and renal transplantation. Dialysis is expensive (($USD15-25,000/year/patient), results in a poor quality of life and a high yearly mortality rate ((16%). Kidney transplantation, although requiring immunosuppression, is preferable to dialysis, but due to a decrease in cadaveric donors worldwide only a quarter of patients awaiting transplantation will receive this treatment. Compounding the problem is a steady increase in the rate of ESRD worldwide primarily due to an increase in Type II diabetes. Several alternative treatment options are being investigated to treat chronic renal disease, including pig xenotransplantation and bioartificial kidney devices. In this application we will investigate the ability to treat chronic renal disease using stem cells. Two long-term approaches to renal regeneration will be investigated: de novo renal generation and endogenous renal repair. Both of these will require the induction of embryonic or adult stem cells to adopt a renal progenitor fate and then the isolation of these cells via specific markers. De novo generation of a replacement organ would then involve aggregation of renal progenitors and implantation of these aggregates into the omentum for vascularisation, together with reconnection to the excretory tract via a replacement ureter. Endogenous renal repair would involve the reintroduction and integration of induced and isolated renal progenitor cells into the damaged kidney. To reach these clinical objectives, we propose the following basic research objectives: (1) Use expression profiling to further dissect the processes of commitment to a renal fate during normal development;(2) Examine the potential for embryonic and adult stem cells to be differentiated into the lineages necessary for renal regeneration; (3) Identify novel renal progenitor cell markers and growth factors to assist in the identification, isolation and / or reactivation of renal stem cells; and (4) Utilize pathological and functional assays to determine the in vivo outcomes of de novo organ generation and renal repair. Human ES cell work will be performed using ES01, 02, 03, 04, 05 & 06 listed on the NIH ES cell line registry.